Bipolar is a severe and lifelong illness affecting 4.5% of the population - about 14 million people in the U.S. It is one of the top 10 most disabling medical conditions worldwide according to the World Health Organization. Traditionally, the mood stabilizer lithium (Li) has been used extensively for the treatment of acute mood episodes (mania and depression) and for maintenance prevention of relapse. However, in recent years, second generation antipsychotics (SGAs;e.g., quetiapine [QTP], olanzapine, and aripiprazole) have rapidly supplanted older medications for both acute and maintenance treatment. In fact, QTP has become the most commonly prescribed medication for bipolar disorder. This is true in spite of the observation that treatment with SGAs is associated with significant metabolic and, potentially, cardiovascular risk, owing to their adverse effects of weight gain, dyslipidemias, and type II diabetes. To date, however, there have been no large-scale, randomized comparative effectiveness studies comparing SGA's against older mood stabilizers for the acute or maintenance treatment of bipolar disorder in real-world settings. The comparative risks and benefits of SGAs versus older medications such as Li for bipolar disorder assessed in real-world settings and patients represent public health questions of major significance. Therefore, the primary aim of this study is to evaluate comparative benefits and harms for QTP versus Li in bipolar outpatients over a period of 6 months. QTP and Li will be combined with other medications for bipolar disorder (adjunct personalized treatment [APT], excluding QTP for lithium treated patients and lithium for QTP patients) in parallel with typical clinical practice. A co-primary aim will be to assess the frequency of necessary clinical adjustments (NCAs) of medications for the groups randomized to QTP+APT versus Li+APT. Secondary aims will be to compare the effect of QTP+APT versus Li+APT on: 1. The future risk of cardiovascular disease as measured by change in the Framingham General Cardiovascular Risk Score over the course of 6 months;and 2. Functional status. Exploratory aims will be to assess moderators of response to QTP+APT or Li+APT, to include underserved racial and ethnic minority status, comorbid psychiatric and medical disorders, younger (age >18 and <25 years) and older (>55 years) age. Genetic material will also be collected and sent to the NIMH tissue bank on well-characterized participants with well-defined longitudinal response to QTP+APT or Li+APT for future pharmacogenomic studies. This study has a very high potential to have a major public health impact and to change the treatment of millions of Americans with bipolar disorder. PUBLIC HEALTH RELEVANCE: This study will compare two treatments over 6 months for participants with bipolar disorder who present with at least mild symptoms and who require a change in treatment. The two treatments will be the second generation antipsychotic mood stabilizer quetiapine and the classic mood stabilizer lithium. In addition to quetiapine or lithium, participants can be treated with other medications as needed.